International immunopharmacology · 2025
Discovery of o-aminodiphenyl-based USP7 inhibitor for immune activation and antitumor response in colorectal cancer.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Jia Gang, Wang Yuanying, Zhou Weiwei, Huang Xiaomei, Song Zhiyu
Аннотация
BACKGROUND: Colorectal cancer is a leading cause of cancer mortality, with microsatellite-stable tumors exhibiting poor response to immune checkpoint inhibitors. Ubiquitin-specific protease 7 (USP7) stabilizes programmed death-ligand 1 (PD-L1), promoting immune evasion.
METHODS: Through screening, synthesis, and optimization, we identified an o-aminodiphenyl derivative, U-20, as a potent USP7 inhibitor (IC₅₀ = 83 nM). USP7 inhibition, PD-L1 modulation, and immune activation were evaluated using in vitro enzymatic and cellular assays, T-cell killing assays, and an immunocompetent CT26 colorectal cancer mouse model.
RESULTS: U-20 selectively bound USP7, destabilized PD-L1 via proteasome-mediated degradation, and increased PD-L1 polyubiquitination without affecting transcription. In colorectal cancer cell-T-cell co-cultures, U-20 enhanced CD8+ T-cell cytotoxicity and cytokine secretion (IFN-γ, TNF-α), effects abolished by ubiquitination-resistant PD-L1 mutants. In vivo, U-20 significantly inhibited tumor growth, increased intratumoral CD8+ T-cell infiltration, and elevated effector cytokine levels, without apparent toxicity.
CONCLUSION: U-20 effectively reprograms the colorectal cancer immune microenvironment by blocking USP7-mediated PD-L1 stabilization, thereby restoring antitumor immunity. These findings provide a preclinical rationale for USP7 inhibition as a novel immunotherapeutic strategy for colorectal cancer, particularly in microsatellite-stable disease.
METHODS: Through screening, synthesis, and optimization, we identified an o-aminodiphenyl derivative, U-20, as a potent USP7 inhibitor (IC₅₀ = 83 nM). USP7 inhibition, PD-L1 modulation, and immune activation were evaluated using in vitro enzymatic and cellular assays, T-cell killing assays, and an immunocompetent CT26 colorectal cancer mouse model.
RESULTS: U-20 selectively bound USP7, destabilized PD-L1 via proteasome-mediated degradation, and increased PD-L1 polyubiquitination without affecting transcription. In colorectal cancer cell-T-cell co-cultures, U-20 enhanced CD8+ T-cell cytotoxicity and cytokine secretion (IFN-γ, TNF-α), effects abolished by ubiquitination-resistant PD-L1 mutants. In vivo, U-20 significantly inhibited tumor growth, increased intratumoral CD8+ T-cell infiltration, and elevated effector cytokine levels, without apparent toxicity.
CONCLUSION: U-20 effectively reprograms the colorectal cancer immune microenvironment by blocking USP7-mediated PD-L1 stabilization, thereby restoring antitumor immunity. These findings provide a preclinical rationale for USP7 inhibition as a novel immunotherapeutic strategy for colorectal cancer, particularly in microsatellite-stable disease.